Combination of a selective NMDA NR2B antagonist and an opioid analgesic

ABSTRACT

A combination of a selective NMDA NR2B antagonist and an opioid analgesic is useful in the treatment of pain or nociception.

This is an application under 35 U.S.C. 371 of PCT/GB99/00585 and claimspriority from Great Britain Application No. 9804885.3, filed Mar. 6,1998.

This invention relates to the treatment or prevention of pain ornociception by the administration of a combination of a selective NMDANR2B antagonist and an opioid analgesic.

Pain has been defined as the sensory experience perceived by nervetissue distinct from sensations of touch, pressure, heat and cold. It isoften described by sufferers by such terms as bright, dull, aching,pricking, cutting, burning, etc. This range of sensations, as well asthe variation in perception of pain by different individuals, renders aprecise definition of pain near impossible. Pain as suffering, however,is generally considered to include both the original sensation and thereaction to that sensation. Where pain is “caused” by the stimulation ofnociceptive receptors and transmitted over intact neural pathways, thisis termed nociceptive pain. Alternatively, pain may be caused by damageto neural structures, often manifesting itself as neuralsupersensitivity, and is classed as neuropathic pain.

The level of stimulation at which pain is perceived is referred to asthe “pain threshold”. Where the pain threshold is raised, for instance,by the administration of an analgesic drug, a greater intensity or moreprolonged stimulus is required before pain is experienced. Analgesicsare a class of pharmaceutical agent which, following administration to apatient in need of such treatment, relieve pain without loss ofconsciousness. This is in contrast to other pain-relieving drugs, forexample, general anaesthetics which obtund pain by producing a hiatus inconsciousness, or local anaesthetics which block transmission inperipheral nerve fibres thereby preventing pain.

NMDA (N-methyl-D-aspartate)-type glutamate receptors are believed toplay a pivotal role in the transmission of excitatory signals fromprimary sensory neurones to the brain through the spinal cord (A. H.Dickenson (1990) Trends Pharmacol. Sci., 11. 307-309). NMDA receptorsmediate Ca²⁺influx into neurones, and its receptor-gated channelactivity is blocked by Mg²⁺ in a voltage-dependant manner. Subunits ofthe NMDA receptors are classified into two gene families, i.e., NR1 andNR2. A variety of compounds have been designed as antagonists targetingthese subunits of the NMDA receptor for the treatment ofneurodegenerative disorders, as well as acute and/or chronic pain andhyperalgesia. The NR2B subunit is predominantly expressed in thehippocampus (Ishii et al., (1993), J. Biol. Chem. 268, 2836-2843).

NMDA antagonists such as ketamine, dextromethorphan and CPP are known tohave analgesic properties in man. However, these agents also induceunacceptable side-effects including hallucinations. dysphoria andcognitive and motor disturbances (see Kristensen et al., 1992, Pain, 51,249ff, Price et al., 1994, Pain, 59, 165ff and Max et al., Clin.Neuropharmacol., 118, 360ff). In preclinical studies, dextromethorphanhas been reported to potentiate the antinociceptive effects of NSAIDSand morphine (Price et al.,1996, Pain, 68, 119-127; Mao et al., 1996,Pain, 67, 361-368). However, since dextromethorphan can induce adverseeffects at analgesic doses in man, it is not clear from these studieswhether such combinations would still be dogged with unwantedside-effects.

One selective NMDA NR2B antagonist CP-101,606 is known to possessanti-nociceptive activity, see Taniguchi et al., B. J. Pharmacol., 1997,122, 809-812. Potent analgesic activity of this compound was shown inrat hyperalgesic and nociceptive tests at doses showing no behaviouralabnormality.

There is, however, no general teaching in the art that all selectiveNMDA NR2B antagonists are useful as analgesics, nor that they haveimproved motor side-effect profile compared to NMDA/glycine antagonists.Evidence for this is, for the first time, provided herein.

Furthermore there is no suggestion in the art that selective NMDA NR2Bantagonists could potentiate the effects of opioids, such as morphine,thus providing analgesia with suprisingly reduced side-effects, such asmotor-impairment. Thus the safety margin for the use of opioids, such asmorphine, is surprisingly improved. There is no indication in the artrelating to NMDA antagonists that the property of potentiating theaction of morphine could be transferred to compounds selective for theNR2B subunit.

As the present specification surprisingly demonstrates that selectiveNMDA NR2B antagonists possess antinociceptive effects in rat models ofinflammatory and neuropathic pain with a much improved side-effectwindow over non-competitive NMDA antagonists (ataxic/antinociceptive),when combined with an opioid, the combination is better tolerated thanexpected.

The opioid analgesics are a well-established class of analgesic agent.They are also sometimes referred to as opiates although this term shouldbe reserved for chemical relatives of morphine. The term opioid isgenerally accepted to refer in a generic sense to all drugs, natural orsynthestic, with morphine-like actions. The synthetic and semi-syntheticopioid analgesics are derivatives of five chemical classes of compound:phenanthrenes; phenylheptylamines; phenylpiperldines; morphinans; andbenzomorphans. Pharmacologically these compounds have diverseactivities, thus some are strong agonists at the opioid receptors (e.g.morphine); others are moderate to mild agonists (e.g. codeine); stillothers exhibit mixed agonist-antagonist activity (e.g. nalbuphine); andyet others are partial agonists (e.g. nalorphine). Whilst an opioidpartial agonist such as nalorphine, (the N-alkyl analogue of morphine)will antagonise the analgesic effects of morphine, when given alone itcan be a potent analgesic in its own right.

Of all of the opioid analgesics, morphine remains the most widely usedand is a suitable archetype compound. Unfortunately, apart from itsuseful therapeutic properties, morphine also has a number of drawbacksincluding sedation, respiratory depression, decreased gastrointestinalmotility (resulting in constipation) and, in some individuals, nauseaand vomiting may occur. Another characteristic is the development oftolerance and physical dependence which mast limit the clinical use ofsuch compounds. There is therefore a need to develop methods whichenable the clinician to use lower doses of opioid analgesics such asmorphine, thereby reducing the likelihood of adverse effects anddevelopment of tolerance and dependence, and thus avoiding the majorproblem of drug withdrawal associated with cessation of administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the carrageenan-induced mechanical hyperalgesia(plotted as a percent) as a function of NMDA NR2B antagonist dose (mg/kgi.p.).

FIG. 2 is a graph of the percent hyperalgesia as a function of a NOVANR2B antagonist alone, morphine alone, and the combination of morphinewith an NMDA NR2B antagonist.

FIG. 3 is a graph of motor control as a function of a NMDA NR2Bantagonist alone, morphine alone, and the combination of morphine withan NMDA NR2B antagonist.

DESCRIPTION OF THE INVENTION

The present invention accordingly provides the use of a selective NMDANR2B antagonist and an opioid analgesic for the manufacture of amedicament for the treatment or prevention of pain or nociception.

The present invention also provides a method for the treatment orprevention of pain or nociception, which method comprises administrationto a patient in need of such treatment an amount of a selective NMDANR2B antagonist and an amount of an opioid analgesic such that togetherthey give effective pain relief

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a selective NMDA NR2B antagonistand an opioid analgesic, together with at least one pharmaceuticallyacceptable carrier or excipient.

It will be appreciated that the selective NMDA NR2B antagonist andopioid analgesic may be present as a combined preparation forsimultaneous, separate or sequential use for the treatment or preventionof pain. Such combined preparations may be, for example, in the form ofa twin pack.

In a further or alternative aspect of the present invention, there istherefore provided a product comprising a selective NMDA NR2B antagonistand an opioid analgesic as a combined preparation for simultaneous,separate or sequential use in the treatment or prevention of pain ornociception.

The compositions of the present invention are useful for the treatmentof pain of any eitiology, including acute and chronic pain and any painwith an inflammatory component. Examples of acute pain include, inparticular, post-operative pain, migraine, headache and trigeminalneuralgia. Examples of chronic pain include. in particular, painassociated with musculo-skeletal disorders such as rheumatoid arthritis,osteoarthritis, ankylosing spondylitis, sero-negative (non-rheumatoid)arthropathies, non-articular rheumatism and peri-articular disorders,and pain associated with cancer, peripheral neuropathy and post-herpeticneuralgia. Examples of pain with an inflammatory component (in additionto some of those described above) include rheumatic pain, dental painand dysmenorrhoea.

The compositions of the present invention are especially useful for thetreatment of pain where the use of an opioid analgesic is generallyprescribed. By the use of a combination of a selective NMDA NR2Bantagonist and an opioid analgesic in accordance with the presentinvention, it is now possible to treat pain with a sub-maximal dose ofan opioid analgesic thereby reducing the likelihood of side-effectsassociated with opioid analgesic usage (e.g. respiratory depression,constipation, nausea and vomiting, and tolerance and dependence and theassociated problem of drug withdrawal).

A particularly preferred use for a composition of the present inventionis in the treatment or prevention of post-operative pain.

Selective NMDA NR2B antagonists of use in the present invention includeeliprodil (and those of EP-A-109317 and French utility certificate FR 8904835), ifenprodil (and those of French patent FR 5733 M), Ro25-6981(and those of EP-A-648744), compounds disclosed in WO-A-9713769 toPharmacia and CP-101,606 (and those of EP-A-768086). A particularlyfavoured compound is Ro25-6981:

Particularly suitable selective NMDA NR2B antagonists can be identifiedby the following cascade which forms a further feature of the presentinvention. There is accordingly provided an assay for identifying aselective NMDA NR2B antagonist comprising:

(i) determining a compound having an IC₅₀ of less than 100 nM affinityat the human NMDA NR2B receptor and having a greater than 100-foldselectivity for NR2B receptors over human I_((Kr)) cardiac potassiumchannels in radioligand binding studies;

(ii) demonstrating said compound inhibits hyperalgesia with ID₅₀<30mg/kg i.p. or s.c. and has a greater than 10-fold window between dosesproducing antinociception and motor disruption in carrageenan-inducedhyperalgesia in rats;

(iii) determining said compound has an ID₅₀ of less than 30 mg/kg i.p.or s.c. in the rat sciatic nerve ligation assay of neuropathic pain;

(iv) determining said compound has an ID₅₀ of less than 30 mg/kg p.o. inthe rat carrageenan-induced hyperalgesia assays; and

(vi) demonstrating said compound has synergistic antinociceptive effectsin combination with an opioid in an assay of nociception such asinhibition of hyperalgesia induced by carrageenan or Freund's adjuvantor inhibition of allodynia in neuropathic rats.

The compounds of use in this invention may have one or more asymmetriccentres and can therefore exist as enantiomers and possibly asdiastereoisomers. It is to be understood that the present inventionrelates to the use of all such isomers and mixtures thereof.

Suitable pharmaceutically acceptable salts of the selective NMDA NR2Bantagonists of use in the present invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundwith a solution of a pharmaceutically acceptable non-toxic acid such ashydrochloric acid, fumaric acid, maleic acid, succinic acid, aceticacid, citric acid, tartaric acid, carbonic acid or phosphoric acid.Salts of amine groups may also comprise the quaternary ammonium salts inwhich the amino nitrogen atom carries an alkyl, alkenyl, alkynyl oraralkyl group. Where the compound carries an acidic group, for example acarboxylic acid group, the present invention also contemplates saltsthereof, preferably non-toxic pharmaceutically acceptable salts thereof,such as the sodium, potassium and calcium salts thereof.

Suitable opioid analgesics of use in the present invention includemorphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone,hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine,butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine,propoxyphene and pentazocine; or a pharmaceutically acceptable saltthereof.

A particularly preferred opioid analgesic of use in the presentinvention is morphine; or a pharmaceutically acceptable salt thereof.

Suitable pharmaceutically acceptable salts of the opioid analgesics ofuse in the present invention include those salts described above inrelation to the salts of selective NMDA NR2B antagonists.

Preferred salts of opioid analgesics of use in the present inventioninclude morphine sulphate, morphine hydrochloride, morphine tartrate,codeine phosphate, codeine sulphate, dihydrocodeine bitartrate,diacetylmorphine hydrochloride, hydrocodone bitartrate, hydromorphonehydrochloride, levorphanol tartrate, oxymorphone hydrochloride,alfentanil hydrochloride, buprenorphine hydrochloride, butorphanoltartrate, fentanyl citrate, meperidine hydrochloride, methadonehydrochloride, nalbuphine hydrochloride, propoxyphene hydrochloride,propoxyphene napsylate (2-naphthalenesulphonic acid (1:1) monohydrate),and pentazocine hydrochloride.

A particularly preferred opioid analgesic of use in the presentinvention is morphine hydrochloride.

As stated above, the selective NMDA NR2B antagonist and opioid analgesicmay be formulated in a single pharmaceutical composition oralternatively in individual pharmaceutical compositions forsimultaneous. separate or sequential use in accordance with the presentinvention.

Preferably the compositions according to the present invention are inunit dosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water. to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings. such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil. is well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Preferred compositions for administration by injection include thosecomprising a selective NMDA NR2B antagonist, as the active ingredient.in association with a surface-active agent (or wetting agent orsurfactant) or in the form of an emulsion (as a water-in-oil oroil-in-water, emulsion).

Suitable surface-active agents include, in particular, non-ionic agents,such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) andother sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with asurface-active agent will conveniently comprise between 0.05 and 5%surface-active agent, and preferably between 0.1 and 2.5%. It will beappreciated that other ingredients may be added, for example mannitol orother pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fatemulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ andLipiphysan™. The active ingredient may be either dissolved in apre-mixed emulsion composition or alternatively it may be dissolved inan oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil.corn oil or almond oil) and an emulsion formed upon mixing with aphospholipid (e.g. egg phospholipids, soybean phospholipids or soybeanlecithin) and water. It will be appreciated that other ingredients maybe added, for example gylcerol or glucose, to adjust the tonicity of theemulsion. Suitable emulsions will typically contain up to 20% oil, forexample, between 5 and 20%. The fat emulsion will preferably comprisefat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, andhave a pH in the range of 5.5 to 8.0.

Particularly preferred emulsion compositions are those prepared bemixing a selective NMDA NR2B antagonist with Intralipid™ or thecomponents thereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present invention further provides a process for the preparation ofa pharmaceutical composition comprising a selective NMDA NR2B antagonistand an opioid analgesic, which process comprises bringing a selectiveNMDA NR2B antagonist and an opioid analgesic into association with apharmaceutically acceptable carrier or excipient.

When administered in combination, either as a single or as separatepharmaceutical composition(s), the selective NMDA NR2B antagonist andthe opioid analgesic are presented in a ratio which is consistent withthe manifestation of the desired effect. In particular, the ratio byweight of the selective NMDA NR2B antagonist to the opioid analgesicwill suitably be approximately 1 to 1. Preferably this ratio will bebetween 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and100 to 1.

A suitable dosage level for the selective NMDA NR2B antagonist is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen of up to 6 times per day, preferably 1 to 4times per day.

The opioid analgesic may be administered at a dosage level up toconventional dosage levels for such analgesics, but preferably at areduced level in accordance with the present invention. Suitable dosagelevels will depend upon the analgesic effect of the chosen opioidanalgesic, but typically suitable levels will be about 0.001 to 25 mg/kgper day, preferably 0.005 to 10 mg/kg per day, and especially 0.005 to 5mg/kg per day. The compound may be administered on a regimen of up to 6times per day, preferably 1 to 4 times per day.

It will be appreciated that the amount of a selective NMDA NR2Bantagonist and opioid analgesic required for use in the treatment orprevention of pain or nociception will vary not only with the particularcompounds or compositions selected but also with the route ofadministration. the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

The following examples illustrate pharmaceutical compositions accordingto the invention.

These formulations may be prepared with separate active ingredients orwith with a combination of active ingredients in one composition. Insuch combined preparations, the ratio of selective NMDA NR2B antagonistto opioid analgesic will depend upon the choice of active ingredients.

EXAMPLE 1A Tablets Containing 1-25 mg of Compound

Amount mg Active Ingredients(s) 1.0 2.0 25.0 Microcrystalline cellulose20.0 20.0 20.0 Modified food corn starch 20.0 20.0 20.0 Lactose 58.557.5 34.5 Magnesium Stearate 0.5 0.5 0.5

EXAMPLE 1B Tablets Containing, 26-100 mg of Compound

Amount mg Active Ingredients(s) 26.0 50.0 100.0 Microcrystallinecellulose 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0Lactose 213.5 189.5 139.5 Magnesium Stearate 0.5 0.5 0.5

The active ingredient(s) cellulose, lactose and a portion of the cornstarch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0mg, 50.0 mg and 100 mg of the active compound per tablet.

EXAMPLE 2 Parenteral Injection

Amount Active Ingredient(s) 1 to 100 mg Citric Acid Monohydrate 0.75 mgSodium Phosphate 4.5 mg Sodium Chloride 9 mg Water for injection to 10ml

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The active ingredient(s) is (are)dissolved or suspended in the solution and made up to volume.

EXAMPLE 3 Topical Formulation

Amount Active Ingredient(s) 1-10 g Emulsifying Wax 30 g Liquid paraffin20 g White Soft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient(s) is (are) is added and stirring continued until dispersed.The mixture is then cooled until solid.

EXAMPLE 4A (Surface-Active Agent) Injection Formulation

Active Ingredient(s) up to 10 mg/kg Tween 80 ™ up to 2.5% [in 5% aqueousmannitol (isotonic)]

The active ingredient(s) is (are) dissolved directly in a solution ofthe commercially available Tween 80™ (polyoxyethylenesorbitanmonooleate) and 5% aqueous mannitol (isotonic).

EXAMPLE 4B (Emulsion) Injection Formulation

Active Ingredient(s) up to 30 mg/ml Intralipid ™ (10-20%)

The active ingredient(s) is (are) dissolved directly in the commerciallyavailable Intralipid™ (10 or 20%) to form an emulsion.

EXAMPLE 4C Alternative (Emulsion) Injectable Formulation

Amount Active Ingredient(s) 0.1-10 mg Soybean oil 100 mg EggPhospholipid 6 mg Glycerol 22 mg Water for injection to 1 ml

All materials are sterilized and pyrogen free. The active ingredient(s)is (are) dissolved in soybean oil. An emulsion is then formed by mixingthis solution with the egg phospholipid, glycerol and water. Theemulsion is then sealed in sterile vials.

The following Example illustrates that selective NMDA NR2B receptorantagonists have a reduced motor side-effect profile when compared withNMDA/glycine antagonists.

EXAMPLE 5

The present Example examined whether NMDA NR2B receptor antagonists havean improved therapeutic window over unselective NMDA/glycine antagonistsand other ion channel blockers including lamotrigine and gabapentin, bycomparing their anti-algesic effects with their liability to inducemotor impairment in rats. Anti-algesic activity was assessed using anassay of neuropathic pain in rats (sciatic nerve ligation) and in acarrageenan-induced hyperalgesia assay. Motor impairment was measuredusing an accelerating rotarod.

Methods

For sciatic nerve ligation, male Sprague Dawley rats (180-220 g) wereanaesthetised with isofluorane, the left sciatic nerve exposed and 4chromic catgut (4.0) ligatures were tied loosely around the nerve(spaced 1-2 mm apart) immediately proximal to the point of trifurcation.In sham-operated animals, the same dissection was performed but withoutligation. Responses to mechanical pressure were assessed 7 days afterligation using a modified Randall-Selitto algesiometer in which constantforce of 40 mmHg was applied to the hind paw and the latency to strugglewas recorded as the reaction time. Mechanical allodynia was defined asthe difference in reaction time for sham and ligature rats. Reactiontimes for drug treated rats were expressed as a percentage of thisresponse. Compounds were administered 1 h before the test. In thecarrageenan-induced hyperalgesia assay, male Sprague Dawley rats(100-120 g) received an intraplantar injection of carrageenan (4.5 mg)and mechanical thresholds were determined 3 h later using a modified UgoBasile Algesiometer. Control rats received saline (0.15 ml i.pl.).Hyperalgesia was defined as the difference in vocalisation threshold forsaline- and carrageenan-injected rats. Paw pressure scores fordrug-treated rats were expressed as a percentage of this response.Compounds were administered 2 h after carrageenan. To determine theeffects of the compounds on motor co-ordination, male Sprague Dawleyrats (160-180 g) were first trained to remain for 120 s on the rotarodapparatus revolving at 12 r.p.m. on the morning before the test. Animalsthen received drug treatments and 1 h later were placed on anaccelerating rotarod (increasing from 4-40 r.p.m. during a 5 min period)and the time the rats were able to remain on the rotarod recorded.Lamotrigine, gabapentin and (±)-CP-101,606 were suspended in 0.5%methocel and administered orally (1 ml/kg). Ifenprodil, L-701.324,L-687,414 and (±)-Ro25-6981 were dissolved or suspended in in 0.5%methocel and administered intraperitoneally (1 ml/kg). MK-801 wasdissolved in distilled water and given i.p. (1 ml/kg). Doses ofcompounds refer to the free base.

Results

Anti-algesia Studies

Animals with sciatic nerve ligation exhibited mechanical allodynia asmeasured by the reduction in the reaction time to withdraw the injuredlimb from the paw pressure apparatus Reaction times for sham andligature rats were typically 22±1s and 8±1s. respectively. The NMDA NR2Bantagonists, (±)-CP-101,606 and (±)-Ro25-6981, the NMDA/glyciniereceptor antagonist L-701,324 and partial agonist L-687,414 and thenon-competitive NMDA antagonist MK-801 dose-dependently reversedmechanical allodynia induced by sciatic nerve ligation (Table 1).Similarly. the novel anti-convulsant drugs, lamotrigine and gabapentin,and the vasodilator ifenprodil, which has affinity for the NMDA NR2Breceptor, reversed mechanical allodynia. The order of potency was:MK-801>L-701,324>(±)-Ro25-6981>(±)-CP-101,606>ifenprodil>L-687,414>lamotrigine>gabapentin.

Intraplantar injection of carrageenan (4.5 mg) induced marked paw oedemaand hyperalgesia to mechanical compression of the inflamed hind paw. Allthe compounds caused a dose-dependent inhibition of mechnicalhyperalgesia induced by carrageenan (Table 1). The order of potency was:MK-801>L-701,324>(±)-Ro25-6981>ifenprodil>(±)-CP-101,606>L-687,414=gabapentin>lamotrigine.

Effects on Behaviour and Motor Co-ordination

Vehicle-treated rats were able to remain on the accelerating rotarod forapproximately 140 s. MK-801 dose-dependently induced impairments inrotarod performance with an ID₅₀ of 0.22 mg/kg i.p. Body rolling. andhead weaving were also observed following 0.3 and 1 mg/kg doses ofMK-801. The NMDA/glycine receptor antagonist L-701,324 and partialagonist L-687,414 also induced rotarod deficits (ID₅₀ of 1.9 mg/kg i.p.and 53.3 mg/kg i.p.); ataxia was evident at 10 and 30 mg/kg i.p. ofL-701,324 and L-687,414 induced body rolling and ataxia at 100 and 300mg/kg i.p. Ifenprodil caused approximately 50% impairment in rotarodperformance at 50 mg/kg, however, severe adverse effects were alsoobserved at this dose (ptosis, pilorecetion, hypoactivitly andhyperventilation). Gabapentin caused motor impairments (ataxia) at dosesof 30-300 mg/kg (ID₅₀ for rotarod was 133 mg/kg i.p.). Administration oflamotrigine at 500 mg/kg p.o. caused a 40% inhibition in the time spenton the rotarod: no other effects were observed at this dose. Similarly,(±)-Ro25-6981 induced a 47% inhibition of rotarod performance at a (loseof 100 mg/kg i.p. (±)-CP-101,606 did not inhibit motor performance onthe rotarod up to 300 mg/kg p.o.; in fact, there was a significantincrease in latency following 300 mg/kg dose compared to vehicle-treatedrats.

The ratios for the ID₅₀ inducing motor impairment and inhibition ofallodynia in neuropathic rats were at least 4 fold greater for the NMDANR2B receptor antagonists, (±)-CP-101,606 (ratio>49) and (±)-Ro25-6981(ratio>26), than were found for MK-801 (ratio 1.1), the NMDA/glycineantagonists (ratio<6), gabapentin (ratio 1.5) and ifenprodil (ratio5.3). Lamotrigine had a similar profile to that of the NMDA NR2Breceptor antagonists (ratio>45).

Conclusions

These data suggest that NMDA NR2B antagonists may be useful for treatingneuropathic pain in man with an improved therapeutic window overclinically used unselective ion channel blockers.

TABLE 1 Summary of the anti-algesic and ataxic properties of NMDAreceptor antagonists and other ion channel blockers ID₅₀ (mg/kg) MotorIm- Antinociception pairment Ratio Rat Rat Rat Rotarod/Rat LigationCarrageenan Rotarod Ligation Lamotrigine (p.o.) 11 207 >500 >45Gabapentin (p.o.) 87 50 133 1.5 Ifenprodil (i.p.) 9.5 17 ≧50 5.3 MK-801(i.p.) 0.19 0.21 0.22 1.1 L-701,324 (i.p.) 2.6 2.5 1.9 0.7 L-687,414(i.p.) 9.8 50 53 5.4 (±)-CP-101,606 (p.o.) 6.1 37 >300 >49 (±)-Ro25-6981(i.p.) 3.8 5.7 ≧100 ≧26

The following Example demonstrates the synergistic antinociceptiveeffects of a combined treatment of the selective NMDA NR2B antagonist(±)-Ro25-6981 with morphine.

EXAMPLE 6

The present Example examined whether the NMDA NR2B antagonist(±)-Ro25-6981 could potentiate the antinociceptive effects of morphinein an assay of inflammatory hyperalgesia in rats to determine whethersuch combination therapies may provide improved analgesic efficacy withreduced side-effects in man.

Methods

Male Sprague Dawley rats (100-120 g) received an intraplantar injectionof carrageenan (4.5 mg) and mechanical thresholds were determined 3 hlater using a modified Ugo Basile Algesiometer. Control rats receivedsaline (0.15 ml i.pl.). Hyperalgesia was defined as the difference invocalisation threshold for saline- and carrageenan-injected rats. Pawpressure scores for drug-treated rats were expressed as a percentage ofthis response. Compounds were administered 2 h after carrageenan. Todetermine the effects of morphine and (±)-Ro25-6981 on motorco-ordination, male Sprague Dawley rats (160-180 g) were first trainedto remain for 120 s on the rotarod apparatus revolving at 12 r.p.m. onthe morning before the test. Animals then received drug treatments and 1h later were placed on an accelerating rotarod (increasing from 4-40r.p.m. during a 5 min period) and the time the rats were able to remainon the rotarod recorded.

(±)-Ro25-6981 was suspended in 0.5% methocel and administeredintraperitoneally (1 ml/kg). Morphine HCl was dissolved in saline andgiven subcutaneously (1 ml/kg). Doses of compounds refer to the freebase.

Results

Effect of Ro25-6981 on Carrageenan-Induced Hyperalgesia

Intraplantar injection of carrageenan (4.5 mg) induced marked paw oedemaand hyperalgesia to mechanical compression of the inflamed hind paw.Intraperitoneal (i.p.) administration (±)-Ro25-6981 caused adose-dependent reversal of mechanical hyperalgesia induced bycarrageenan at doses of 10 and 30 mg/kg (FIG. 1). A dose of 1 mg/kg waschosen for combination experiments as this did not cause significantantinociception.

Combination of Ro25-6981 and Morphine oil Carrageenan-InducedHyperalgesia

Subcutaneous (s.c.) administration of morphine alone at 1 mg/kgcompletely reversed mechanical hyperalgesia induced by carrageenanwhereas lower doses of 0.1 and 0.3 mg/kg were without effect (FIG. 2).Combined-administration of a subthreshold dose of (±)-Ro2,5-6981 (1mg/kg, i.p.) with a subthreshold doses of morphine (0.1 and 0.3 mg/kg)resulted in a significantly greater inhibition of hyperalgesia (FIG. 2).The percent inhibition following a dose of 0.1 mg/kg of morphine wasincreased from 11% to 80% and following a dose of 0.3 mg/kg from 31% to94%.

Combination of Ro25-6981 with Morphine on Rotarod Performance

Treatment with (±)-Ro25-6981, (1 mg/kg i.p.) alone had no effect onrotarod performance (FIG. 3). Treatment with morphine alone at 3 mg/kgs.c. induced a significant impairment in rotarod performance whereaslower doses of 0.3 and 1 mg/kg had no effect (FIG. 3). Similarly, whencombined with (±)-Ro25-6981 (1 mg/kg i.p.), the minimum effective doseof morphine causing rotarod disruption was 3 mg,/kg (FIG. 3).

Conclusions

These data demonstrate that administration of (±)-Ro25-6981, at a dosethat is ineffective by itself, can markedly potentiate theantinociceptive effects of morphine. In contrast, there was nosignificant interaction between (i)-Ro25-6981 (1 mg/kg) and morphine(0.3-3 mg/kg) on the rotarod indicating that motor impairment induced bymorphine is not potentiated by (±)-Ro25-6981.

What is claimed is:
 1. A synergistic product consisting essentially of a synergistic amount of a selective NMDA (N-methyl-D-aspartate) NR2B subtype antagonist and an opioid analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment of pain or nociception, wherein said selective NMDA NR2B subtype antagonist is eliprodil.
 2. The synergistic, product according to claim 1 wherein the opioid analgesic is morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof.
 3. The synergistic product according to claim 2 wherein the opioid analgesic is morphine or a pharmaceutically acceptable salt thereof.
 4. A synergistic pharmaceutical composition consisting essentially of a synergistic amount of a selective NMDA (N-methyl-D-aspartate) NR2B subtype antagonist and an opioid analgesic together with at least one pharmaceutically acceptable carrier or excipient, wherein said NMDA NR2B subtype antagonist is eliprodil.
 5. A method for the treatment or prevention of pain or nociception, which method comprises administering a synergistic pharmaceutical composition of claim 4 a synergistic to a patient in need of such treatment of amount of a selective NMDA (N-methyl-D-aspartate) NR2B subtype antagonist and an opioid analgesic such that together they give effective pain relief, wherein said selective NMDA NR2B subtype antagonist is eliprodil.
 6. A process for the preparation of a synergistic pharmaceutical composition consisting essentially of a synergistic amount of a selective NMDA (N-methyl-D-aspartate) NR2B subtype antagonist and an opioid analgesic, which process comprises bringing a selective NMDA NR2B antagonist and an opioid analgesic into association with a pharmaceutically acceptable carrier or excipient, wherein said selective NMDA NR2B subtype antagonist is eliprodil. 